1. Field of the Invention
This invention pertains generally to methods for treating inappropriate cardiac conduction, and more particularly to a method for identifying the atrio-ventricular junction in the heart and injecting a pharmacological or biological substance into the junction to enhance or retard conduction of electrical impulses.
2. Description of the Background Art
The cardiac conduction system is responsible for the generation and transmission of the electrical activity that initiates myocardial contraction. Cardiac arrhythmias resulting from electrical conduction disturbances can lead to life threatening ventricular tachyarrhythmias, hemodynamically compromising bradycardias, and heart block.
Within the cardiac conduction system, lies the strategically positioned atrio-ventricular (AV) junction comprising the AV node and the bundle of His. This electrically insulated conduit between the atrium and ventricle synchronizes atrial and ventricular contraction. Perturbations of this strategic cardiac structure produce either (1) rapid transmission of atrial impulses which leads to a rapid ventricular response or (2) heart block which creates atrial and ventricular dissociation.
Tachycardia, which results from enhanced AV conduction, is commonly treated with antiarrhythmic drugs, radiofrequency modification of the AV node, or complete AV junction ablation with the implantation of a permanent pacemaker. Heart block, often a function of the general aging process, is commonly treated by the implantation of a permanent pacemaker. While these current therapies are generally effective in treating the conduction disturbances of the AV junction, their negative aspects include: (1) side effects and proarrhythmias from the antiarrhythmic drugs, (2) irreversible tissue damage caused by radiofrequency modulation/ablation, (3) implantation of a mechanical device and its need for replacement every 5 to 7 years, (4) surgical and mechanical complications resulting from the implantation of the device, (5) negative physical and psychological effects of an implanted mechanical device and (6) a prevalent need to use concurrent antiarrhythmic therapy, radiofrequency modulation/ablation and the implantation of a permanent pacemaker.
Therefore, there is a need for an alternative therapy for treatment of conduction abnormalities that overcomes the negative aspects of current treatment methods. One such approach would be to utilize biologically active substances; for example, cell transplantation or gene therapy. In contrast to the conventional treatment modalities which attempt to simulate the physiological process of the heart, the application of biologically active substances to correct conduction disturbances would enhance the natural physiological processes.
Clearly, organ transplantation has become an accepted method for the replacement of diseased nonfunctional tissue. More recently, however, the use of autologous cellular transplantation for the correction of tissue defects has emerged as a potential therapeutic alternative. For example, healthy chondrocytes have been cultured and transplanted to repair cartilage defects in the knee (Brittberg et al., 1994). Additionally, transplantation of fetal brain cells have been shown to improve certain neurological disorders (Peschanski et al., 1994; Koutouzis et al, 1994).
With the recent demonstration that individual fetal cardiac cells can be successfully transplanted into live adult mice and form the tight bonds within the host heart cells needed for the transplants to contribute to pumping blood (Soonpass et al, 1994), the concept of direct myocardial reconstruction is now a viable option. Independent investigators have begun to explore the utility of fetal myocardial tissue (Leor et al., 1996; Scorsin et al., 1996), genetically modified cardiac myocytes (Gojo et al., 1996; Aoki et al., 1997) and the use of skeletal muscle cell transplantation in the repair of myocardial infracted tissue (Murry et al., 1996).
In the future, patients with severe heart damage may be candidates for cardiac cell transplantation. However, the large amount of transplanted tissue required to augment cardiac mechanical function would not be insignificant. In contrast, the use of cellular transplantation to make significant alterations in cardiac conduction would not require large amounts of grafted tissue. A growing body of evidence suggests that grafted cardiomyocytes (Koh et al., 1993; Soonpaa et al., 1994) do not cause cardiac arrhythmias or negatively influence the host's cardiac rhythm. These observations suggests that the use of grafted cardiac tissue could be utilized as a primary treatment of cardiac conduction disturbances. In addition, the survival of transplanted cells may be enhanced by the inhibition of cell-mediated immunity by the transfer gene products such as transforming growth factor-beta 1 (Qin et al., 1996), interleukin-2 (Gitlitz et al., 1996) and interleukin-10 (Qin et al., 1996).
Genetic identification of the genes responsible for the inherited forms of sudden death (Keating et al), identification of a genetic locus for heart block (Brink et al., 1995) and a familial form of atria fibrillation (Brugada et al, 1997) further enhances the possibility of a molecular genetic approach for the treatment of arrhythmias.
Preclinical studies have already demonstrated the ability to alter cardiac cell physiology with the transfer of sarcoplasmic reticulm calcium ATPase (Hajjar et al., 1997), improve myocardial function following ischemia with angiogenic factors as basic fibroblast growth factor and vascular endothelial growth hormone (Pearlman et al., 1995; Banai et al., 1994; Sellke et al., 1996; Padua R. R.; Sethi R.; Dhalla et al., 1995), enhancement of myocardial function resulting from the over-expression of a beta-adrenergic receptor gene (Milano et al., 1994), alter heart failure with the expression of beta-adrenergic receptors (Ping et al., 1996), and repair myocardial necrosis with muscle growth factors (Murry et al., 1996). Over-expression of a potassium channel by using a replication deficient adenovirus highlights the plausibility to alter cardiac excitability (Johns et al., 1995). In addition, tetracycline-regulation of gene expression is possible which would be useful for gene-transfer based therapies (Fishman et al., 1994).
The field of cardiovascular gene transfer has developed rapidly during the past 5 years (Nable 1995). A recent study has demonstrated that the direct intramyocardial injection of a gene regulating muscle development induced the formation of muscle products in a peri-infarct zone (Murry et al., 1996). This study demonstrates the feasibility for a therapeutic role for gene transfer in myocardial repair. Additionally, in the field of vascular diseases, fervent efforts to provide gene transfer of recombinant DNA and other nucleic acids in blood vessels in vivo has been made to develop new therapeutic strategies for the treatment of vascular diseases.
However, regardless of the specific therapy to be delivered to cardiac tissue, whether cellular components or genetic material, a system must be provided for delivery of these substances into the myocardial matrix. Gene transfer by systemic intravenous administration has been tried, but large doses are required and there is a potential for systemic toxicity since the entire body is exposed to the genetic material. This has led to the development of several local intravascular delivery systems such as the use of vascular stents (Tanguay et al., 1994), coronary artery infusion catheters (Kaplitt et al, 1996), polymer coated angioplasty balloons (Takeshita et al., 1996) or prosthetic grafts for the delivery of gene products. Still, while these devices seem promising in their ability to deliver molecular genetic products to the vascular endothelium, it does not appear possible to use the vascular system to deliver genetic material directly into myocardial tissue, and certainly not any way which will achieve adequate control over the distribution of material to specific anatomic and electrophysiologically determined regions such as the right atrium for the sinus node, the AV junction for control of ventricular rate nor the focus of ventricular tachycardia at the border zone of an infarct in the left ventricle.
Initial experimental studies have demonstrated the feasibility of expressing reporter genes in the myocardium by direct injection of the molecular genetic material (Gal et al., 1993; Kirshenbaum et al., 1993; Guzrnan R. J.; Lemarchand et al., 1993; Kass-Eisler et al., 1993; Barr et al., 1994). The concept that gene therapy can be delivered through a standard hollow needle directly puncturing myocardial tissue has been demonstrated by the use of transthoracic delivery of gene products into the myocardium and by the percutaneous delivery of molecular genetic products (Magovern et al., 1996, Li et al., 1995). These and other studies are exciting because they lend support to the concept of a catheter based delivery system for the employment of molecular genetic products. The limitation of the catheter based delivery systems presently used for the delivery of genetic materials is the inability of these catheters to detect areas of electrical abnormalities within the myocardium. Percutaneous steerable catheter based delivery systems with the ability to measure intracardiac electrograms have been developed for the employment of sclerosing agents such as ethanol. However, these devices also lack the sophistication for the accurate delivery of biologically active substances to specific anatomical structures such as the AV node.
Direct injections of antiarrhythmic agents and sclerosing agents have been injected into the AV node. However, thoracotomies were required. In addition, investigators have employed many techniques to interrupt conduction by damaging specialized muscle along the AV conduction axis (Stanzl et al., 1955). In early studies, complete heart block was produced surgically (Scherlag et al, 1967; Steiner et al., 1968; Shiang et al., 1977; Giannelli et al., 1967;Harrison et al., 1977). Catheter-directed instillation of necrosis-inducing substances, such as ethanol, has also been reported (Wang et al., 1992). More recently, percutaneous vascular access has enabled closed-chest techniques for creation of complete heart block (Fisher et al., 1966; Gallagher et al., 1982).
Traditionally, fluoroscopy in combination with intracardiac electrograms had been used as a method to approximate the general area containing the AV junction. This method is adequate for assessing atrioventricular conduction and/or performing catheter ablation of the AV junction; however, fluoroscopy does not allow the precision to consistently inject substances confined to the AV junction. Therefore, to successfully administer pharmacological or biological substances to the AV junction with the intent of being able to modulate or re-establish AV conduction, a more precise means of identifying the AV junction is required. Accordingly, there is a need for a method of identifying the AV junction and delivering biologically active substances into the AV junction to enhance or retard conduction of electrical impulses. The present invention satisfies those needs, as well as others, and overcomes the deficiencies found in conventional forms of treatment.